Synthetic prostaglandins

ABSTRACT

SYNTHETIC PROSTAGLANDINS ARE SYNTHESIZED FROM O-METHOXYPHENYL ACETIC ACID BY INTRODUCTION OF A PROPER ACID SIDE CHAIN, CONVERSION OF THE AAROMATIC NUCLEUS TO THE CYCLOPENTANE NUCLEUS AND INTRODUCTION OF THE SECOND SIDE CHAIN NOVEL COMPOUNDS HAVING A HIGH LEVEL OF BIOLOGICAL ACTIVITY ARE CLAIMED

United States Patent O 3,799,967 SYNTHETIC PROSTAGLANDINS Robert B. Morin, Middleton, Wis., Douglas 0. Spry, Indianapolis, and Kenneth L. Hauser, Greencastle, Ind., and Richard A. Mueller, Glencoe, Ill., assignors to Eli Lilly and Company, Indianapolis, Ind.

No Drawing. Original application Dec. 16, 1968, Ser. No. 784,225, now Patent No. 3,644,502. Divided and this application Oct. 8, 1971, Ser. No. 187,830

Int. Cl. C07c 69/74, 61 /36' US. Cl. 260-468 D ABSTRACT OF THE DISCLOSURE Synthetic prostaglandins are synthesized from o-methoxyphenyl acetic acid by introduction of a proper acid side chain, conversion of the aromatic nucleus to the cyclopentane nucleus, and introduction of the second side chain. Novel compounds having a high level of biological activity are claimed.

CROSS-REFERENCE This application is a division of our copending application Ser. No. 784,225, filed Dec. 16, 1968, now Pat. No. 3,644,502.

BACKGROUND OF THE INVENTION The prostagland'ms are members of a new hormonal system, the discovery of which dates back to 1930 when physiological effects which were later found to be ascribable to prostaglandins were reported. The members of this family are C unsaturated acids containing a fivemembered ring in the structure. A number of naturally occurring prostaglandins have been reported to date.

Members of the prostaglandin family have been shown to be very potent physiologically. Certain aspects of this work are described by Bergstrom, Science 157, 382 1967) Among the effects that have been shown for prostaglandins are a marked lowering of blood presure, either contraction or relaxation of smooth muscle tissue, and inhibition of the release of free fatty acids from fat pads. For example, infusion of PGE, in humans resulted in an increase in heart rate and a fall in arterial blood pressure.

Although the prostaglandins have been found in a number of tissues, their concentrations in these tissues are extremely small. For example, 13 different prostaglandins have been found in a total concentration of about 300 micrograms per milliliter of human seminal plasma. This is by far the highest concentration observed in any tissue to date. Because of these extremely low concentrations it is impossible to obtain sufiicient quantities of the prostaglandins from natural sources. Among the more recent approaches to prostaglandin synthesis are those reported by E. J. Corey and coworkers, J. Am. Chem. Soc. 90, 3245 and 3247 (1968).

SUMMARY We have now discovered a new synthetic route to members of the prostaglandin family from o-methoxyphenylacetic acid by introduction of a proper acid side cha n, conversion of the aromatic nucleus to'the cyclopentane nucleus, and introduction of the second side chain. By

2 Claimsice wherein R is hydrogen ormethyl.

DESCRIPTION OF THE PREFERRED EMBODIMENT The starting material for our synthesis is o-methoxyphenylacetic acid. This material is available commercially or may be readily synthesized from o-hydroxyphenylacetic acid by formation of the methyl ether by any convenient means such as, for example, treatment with dimethyl sulfate. The series of reactions involved in our synthesis may be depicted by the following schematic representation.

0 CHzCOzH A CH2 X -0 OCH. OCH:

v. 0 3o 0 II 0,CH: II

III

. p I 131 o I 46 CHaJ'kCHzhCOgM V ocH.

CH2)CO2H F CH2 (CHl)(CO2H E OCH; OCH] 50 VI I V v GHzltCOzHx ,1

. vnr

g (CHz) COzR H cmomompooza I L[ noon. 0 K -o M 4, CH:

XI X

(CH:)OOR CH:)aC 01R -0 0 0 I H l O\ Hg 0 CH3 CH:

XII XIII M l O OH CH=CH C5Hu CH=CH$HC5H11 cH, ,oo2R CH2)nCOzR N O O 1 O 4H1 1H; as. cit.

XIV XV O H C H=C HHCaHn CHzhCOz R XVI (fi-(CHIXCOgR L t l XXI XVII XXII Step A Step B It is also well known to react an acid halide with an enamine of cyclopentanone to prepare a compound of the type depicted by Formula III. Enamines are obtained by the reaction of secondary amines with ketones. We have found the morpholino enamine of cyclopentanone to be particularly useful in our process. Other enamines that might be employed include, for example, the pyrrolidino enamine and the piperidino enamine of cyclopentanone. The reaction of the enamine with the acid halide proceeds in the presence of a tertiary amine such as triethyl amine. This well-known procedure is described, for example, in Org. Syn. 41, 65. The reaction of the enamine with the acid halide actually results in an intermediate compound which must be further treated to obtain Compound III.

Step C To obtain Compound III from the intermediate obtained in Step B it is necessary to treat the intermediate with a mineral acid. This step is also a well-known step in the reaction of enamines with acid halides.

Step D The cyclopentanone ring of Compound III is opened by treatment with a strong base. The product from this ring opening is the salt of the keto acid as depicted by Formula IV. This cleavage is the well-known base cleavage of 1,3-diketones as described in J. Am. Chem. Soc. 67, 2204 (1945). The reaction is a well-known synthetic tool and is utilized by us in the preparation of the acid side chain.

Step E Step E is the addition of a mineral acid to the product from Step D in order to obtain the free carboxylic acid depicted by Formula V from the salt depicted by Formula IV. No further explanation of this reaction is necessary. The ring opening and subsequent neutralization result in the cleavage of a small amount, about 10 percent, of the ether groups. It is, therefore, advisable to remethylate the free hydroxyl groups at this point.

Step F Step F involves reduction of the carbonyl group in the side chain to a methylene group. This can be accomplished by a Wolff-Kishner reduction. In the process, the hydrazone of the carbonyl group is first formed and this is then decomposed by treatment with a base. Bases that can be employed include potassium hydroxide, sodium hydroxide, potassium ethoxide, sodium methoxide, and similar materials.

Step G Step G also involves reduction; however, in this step the benzene ring is reduced to the cyclohexadiene ring. This reduction is accomplished by means of the Birch reduction in which alkali metal and ammonia are employed as the reducing agent. In our synthesis we have found the use of lithium and ammonia in the presence of isopropyl alcohol as solvent to be most advantageous. In this manner Compound VI is converted to Compound VII.

Step H Cleavage of the ether group in Compound VII results in the formation of the ketone having Formula VIH. We have found the use of oxalic acid to be particularly well suited for this cleavage reaction.

Step I Before proceeding further it is necessary to protect the carboxyl group by the formation of an ester. The ester could have been prepared prior to the ether cleavage of Step H. Since the function of the ester preparation is merely to protect the carboxyl group during subsequent reactions, the particular ester employed is unimportant. However, since it will be necessary to hydrolyze the ester in order to obtain PGB as the free acid, it is suggested that the ester formed be one that may be easily cleaved. Thus R in Formula IX and subsequent formulas may be virtually any group representing the alcohol portion of the ester. For example, R may be an alkylor aralkyl group such as methyl, ethyl, t-butyl, 2,2,2-trichloroethyl, propyl, nonyl, benzyl, and diphenylmethyl. From a practical standpoint, the ease of cleaving the ester prepared must be balanced against the ease of preparation of the ester. We have found the methyl ester to strike such a balance. The methyl ester may be readily prepared by reacting the acid with diazomethane. Other methods of ester preparation are well known to those skilled in the art. The particular method chosen does not affect our synthesis.

Step I It is also necessary at this point to protect the carbonyl group during subsequent reactions. Methods'of protecting carbonyl groups are also well known to those skilled in the art. We have found that we can prepare a ketal-from ethylene carbonate using p-toluenesulfonic acid as catalyst in the presence of ethylene glycol. This ketal serves to protect the carbonyl function but may be readily removed by acid hydrolysis at a later step. Other carbonyl protecting groups may also be employed.

Step K The dialdehyde is then made to undergo ring closure to give a cyclopentenal. This ring closure can occur, and in fact does occur, in two ways so that two isomers, XII and XIII, are obtained. The ring closure can be efiected by treatment with a hindered secondary amine in an inert solvent. Preferred solvents are aromatic hydrocarbons such as benzene, toluene and xylene. The preferred hindered secondary amine is 3-azabicyclo[3.2.2]nonane. 'Other hindered secondary amines such as 2,2,5,5-tetramethylpyrrolidine and 2,2,6,fi-tetramethylpiperidine may also be used. The isomeric cyclopentenals formed are separated from each other by chromatography using a mixture of chloroform and benzene as solvent on a silica column.

Step M r 1 C5H ll- -QH= eH5)l The product of Step M (XIV) is then subjected to one of two alternate paths to obtain the desired product; In one route the side chain carbonyl is first reduced and the ring carbonyl is regenerated by cleaving the ketal to yield 6 Compound XVI. If the ketal is cleaved first and the ring carbonyl is selectively reduced, the product is Compound XXII.

' Step N The next step of our synthesis of XVI is the reduction of. the carbonyl group in the side chain to a hydroxyl group. We have found the use of sodium borohydride in tetrahydrofuran as solvent to be an excellent method of performing this reduction. Skilled chemists will be able to devise other means of reducing this carbonyl group. The means employed is not important to our process so long as the carbonyl group is reduced to a hydroxyl group.

Step 0 In order to regenerate the carbonyl group in the ring the ketal is cleaved by treatment with acid. This acid cleavage of ketals may be effected with a. strong organic acid such as p-toluenesulfonic acid or with a mineral acid such as hydrochloric or phosphoric acid. It is this sensitivity to acid treatment that makes ketals so suitable for the protection of carbonyl groups. We have found this particular ketal cleavage to proceed using p-toluenesulfonic acid in acetone at a temperature of 25 to 30 C.

Step 0' To obtain XXII from XIV we first cleave the ketal to regenerate the ring carbonyl group. This is the same process as Step 0, above. The hydrolysis may be accomplished by the use of a strong sulfonic acid or a strong mineral acid such as p-toluenesulfonic acid, hydrochloric acid, or sulfuric acid.

' Step P The selective reduction of the ring carbonyl group to a hydroxyl group is accomplished by treating with lithium aluminum tri-t-butoxy hydride. The product is Compound XXII.

The preparation of our new prostaglandins will be further illustrated by the following specific examples:

Example 1 Example 2 To the solution from Example 1 was added 96 ml. of

oxalyl chloride and the mixture was heated under reflux for 30 minutes. The benzene was removed by evaporation and the residue was distilled to give 29.3 g. of acid chloride with a boiling point of 1 15 C. The acid chloride was used directly in the next step.

Example 3 The product from Example 2 was dissolved in 100 m1. of dry chloroform and the solution was added over a 12- minute period to a stirred solution of 22.6 g. of the morpholino enamine of cyclopentanone and 14.97 g. of triethylamine in 100 ml. of dry chloroform. During the addition the temperature of the mixture rose to 5 3 C. Upon completion of the addition the mixture was heated and stirred at 60 C. for one hour. To the mixture was then added 60 ml. of 6 N hydrochloric acid and stirring was continued at 55 C. for 30 minutes. The chloroform layer was separated and washed successively with water and saturated sodium bicarbonate solution. This product gave a violet ferric chloride test in ethanol. This solution of (o-methoxyphenyl)acetylcyclopentanone was used directly inthe next step. Example 4 To the solution from Example 3 was added 6.2 g. of sodium hydroxide in 180 m1. of 50 percent ethanol and the mixture was heated under reflux for hours. The solvents were removed by evaporation. The residual oil was dissolved in water and the aqueous solution was washed twice with ether. This aqueous solution was then acidified to a pH of 2 by the addition of concentrated hydrochloric acid. The acidified solution was extracted with ether and the ether extract was washed successively with 1 N hdyrochloric acid, water, and saturated sodium chloride solution, dried, and the ether evaporated to give 24.2 g. of product. The crude product was recrystallized from a mixture of ether and petroleum ether to yield 19.5 g. of purified product having a melting point of 58-60 C.

During the course of this reaction a small amount, perhaps percent, of the methoxy groups are cleaved to the phenol so that it is recommended at this point that the product be remethylated using dimethy sulfate and sodium hydroxide as described in Example 1.

Example 5 The keto acid from Example 4 was subjected to a Wolff- Kishner reduction in accordance with the following procedure. A mixture of 19.5 g. of the keto acid, 87 ml. of diethylene glycol, 32.9 ml. of 85 percent hydrazine hy drate, and 4.6 g. of potassium hydroxide was heated under reflux for three hours. To this mixture was then added 87 ml. of diethylene glycol and 23.9 g. of potassium hydroxide and the mixture was again heated to 200 C. The reaction mixture was cooled and diluted by the addition of 600 ml. of ice and water. The mixture was acidified with 60 ml. of concentrated hydrochloric acid and extracted with ether. The ether extract was evaporated to yield 18 g. of on oil which crystallized on standing. This crystalline product had a melting point of 50-60" C.

Example 6 To a three-neck, l2-liter flask equipped with a Dry Ice condenser and a mechanical stirrer were added 2 l. of ammonia that had been distilled from sodium, 40.12 g. of the acid prepared as in Example 5, and 1 l. of dry isopropanol. To this mixture was slowly added g. of

lithium metal in pieces over a -minute period. When the solution turned white another 10 g. of lithium was added and the mixture was refluxed until it turned white, approximately 25 minutes. To the mixture was slowly added 320 ml. of ethanol followed by 500 ml. of water. The ammonia was removed by evaporation, and the mixture was acidified to a pH of 1 by the addition of concentrated hydrochloric acid while cooling. The alcohol was stripped off and the residue was taken up in ether. The ether solution was washed successively with water and saturated sodium chloride solution, dried, and evaporated to give the cyclohexadiene acid.

Example 7 At this point, the acid from Example 6 was treated with diazomethane to yield 27.6 g. of the methyl ester. The esterification reaction could as easily have been performed at some later step prior to the ozonolysis.

Example 8 The ester from Example 7 was converted to the cyclohexenone by dissolving in 700 ml. of ethanol and adding 85 ml. of water and 40 g. of oxalic acid. The solution was allowed to stand at room temperature for three hours. The ethanol was removed by evaporation and the residue was extracted with ether. The ether extract was washed succes sively with 1 N sodium hydroxide and saturated sodium chloride solution, dried, and evaporated to give 25.05 g. of product. The pure ketone was obtained by distillation on a spinning band column with the product being collected at an overhead temperature of 133 C. and a pressure of 1.5 mm. The nuclear magnetic resonance, infrared, and ultraviolet spectra were consistent with structure IX.

Analysis.Calculated for C H O C, 70.55; H, 9.3 1. Found: C, 70.67; H, 9.48.

Example 9 The ketone from Example 8 was converted to the ketal in the following manner. In a 500 ml. flask were combined 8.0 g. of the keto ester from Example 8, 166 ml. of dried tetrahydrofuran, 43 ml. of dried ethylene glycol, and 9.0 g. of ethylene carbonate. To this mixture was added 86 g. of p-toluenesulfonic acid and the mixture was allowed to stand at room temperature for five hours. At the end of this time the reaction mixture was dissolved in ether and the ether solution was washed successively with 1 N sodium hydroxide, water, and saturated sodium chloride solution, dried, and evaporated to yield 9.6 g. of product. An analytical sample of the ketal was obtained by distillation on a spinning band column at 158 C. and 1.5 mm. pressure. The nuclear magnetic resonance and infrared spectra were consistent with Formula X.

Analysis.-Calculated for C H O C, 68.05; H, 9.28. Found: C, 68.40; H, 9.23.

Example 10 A solution of 2.0 g. of the ketal ester from Example 9 in 140 ml. of chloroform was cooled in a salt-ice bath and ozone was added until the solution turned blue. This required approximately 30 minutes. The reaction mixture was flushed with nitrogen and transferred to a 500 ml. suction flask cooled in an ice bath. The ozonide was decomposed under nitrogen by the addition of 40 ml. of 75 percent acetic acid and 4 g. of zinc dust. This mixture was allowed to stand for one hour and was filtered. The filtrate was washed with water and the pH as adjusted to 7 by the addition of saturated sodium bicarbonate solution. The chloroform layer was then washed with water and sodium chloride solution and dried over sodium sulfate. Evaporation of the chloroform gave 1.8 g. of an oil. The nuclear magnetic resonance and infrared spectra were consistent with the expected dialdehyde having structure XI.

Example 11 A solution of 10.05 g. of the dialdehyde prepared as described in Example 10 in 100 ml. of benzene was added dropwise slowly over a period of one hour to a stirred, cooled (6 C.) solution of 3-azabicyclo[3.2.2]nonane in 600 ml. of benzene. The reaction mixture was stirred under a nitrogen atmosphere for an additional 45 minutes with cooling to the extent that benzene crystals formed. The mixture was slowly warmed to melt the benzene and then adjusted to pH 5 by the addition of 1 N hydrochloric acid. The benzene layer was separated, washed successively with water, sodium bicarbonate solution, and saturated sodium chloride solution, and dried over sodium sulfate. Evaporation of the benzene gave 8.54 g. of a brown oil which was shown to contain the isomeric cyclopentenals having structures XII and XIII as well as some ketal ester having a fully saturated 6-membered ring. This three component mixture was separated by chromatography on a silica column using a weight ratio of product to silica of 1:10 and a solvent consisting of 20 percent chloroform and percent benzene. The column employed was 2 /2 cm. in diameter and 20 cm. long. Product XII was identified by nuclear magnetic resonance, infrared, and ultraviolet spectra, and elemental analysis.

Analysis.-Calculated for C H O C, 64.84; H, 8.16. Found: C, 65.06; H, 7.92.

Example 12 A Wittig reagent to be reacted with compound XII was prepared by the following sequence of steps.

(a) To 18 g. of red mercuric oxide in a 3-neck, 2-liter round-bottom flask, equipped with a mechanical stirrer and a 500 ml. addition funnel were added 12 ml. of anhydrous methanol and 12 ml. of boron trifluoride etherate. The mixture became warm. It was heated with stirring to the boiling point of methanol and then cooled to room temperature. To this catalyst mixture wasadded 295 g. of chloroacetic acid. While the mixture was stirred and cooled 300. g. of .l-heptyne...was.added.dropwise over a one-hour period. The reaction mixture turned a brownblack color. The reactiori'was allowed .to v.proceed at room temperature for an additional hour. The reaction mixture was extracted with 900 ml. of ether andthe ether layer was washed three times with water, three times with sodium bicarbonate solution, and three times with sodium chloride solution, and dried over sodiumsulfate. Evaporation of the ether left a brown oil which was distilled to give 342.8 g. of product boiling at 103 107 C. at 9 mm. pressure. 1

(b) To a stirred, cooled (-5 C.) solution of the 343 g. of the enol acetate from (a) in 50 ml. of chloroform was added dropwise over a three-hour period a solution of 89 ml. of bromine in 50 ml. ofchl orofo rm. The reaction mixture was allowed to stand at room temperature for one hour. The chloroform was then stripped off under vacuum to give a brown solution which was distilled to give 179 g. of product which boiled at 85-118 C. at 25 mm. pressure. This liquid product crystallized at 5 C.

(c) To a solution of 243 g. of triphenyl phosphine in 2 l. of tetrahydrofuran was added with stirring 179 g. of the bromoketone from (b). White crystals precipitated immediately. The reaction was stirred for 8 days. The white crystals were removed by filtration and washed with tetrahydrofuran to give 282 g. of product melting at 192- 193 C. The Wittig reagent was recovered from the salt by dissolving the salt in methanol and adding potassium carbonate solution. This mixture was stirred for approximately five minutes, the methanol was removed 'by stripping, and the mixture was extracted with ether. Evaporation of the ether extract left the desired Wittig reagent.

Example 13 To a solution of 0.141 g. of the cyclopentenal from Example 11 in ml. of 2B ethanol was added a solo-tion of 0.178 g. of the Wittig reagent from Example 12 in 10 ml. of 2B ethanol. This reaction mixture was heated under reflux under a nitrogen atmosphere for 18 hours. The mixture was stripped to drynessand the residue was chromatographed on a silica column using a weight ratio of product to silica of 1:20 and a solvent consisting of 20 percent chloroform and 80 percent benzene. There was obtained a 43 percent yield of a' ketone having structure XIV. The nuclear .magnetic resonance and ultraviolet spectra were consistent with this structure and the molecular weight of 392 was confirmed by a high resolution mass spectrometer.

Analysis.Calculated for C H' O C, 70.37; H, 9.24. Found: C, 70.08; H, 9.45.

Example 14 I A solution of 0.223 g. of the ketone from Example 13 in 10 ml. of dry tetrahydrofuran was added dropwise to a solution of 0.107 g. of sodium borohydride in 10 ml. of dry tetrahydrofuran. The solution turned yellow in color. The reaction mixture was heated under reflux in a nitrogen atmosphere for two hours and was then extracted with ether. The ether extract was washed with saturated sodium chloride solution until it became clear. The ether solution was dried over sodium sulfate and evaporated to give 201 mg. of a yellow oil. This material was chromatographed on silica at a ratio of 1:33 using a solvent which was initially 20 percent chloroform and 80 percent benzene and finishing with 100 percent chloroform. There were obtained 47 mg. of a fast-moving material and 49 mg. of a slower-moving material. These two materials were shown to be diastereoisomers of the desired alcohol. High resolution mass spectrometry showed both to have a molecular weight of 394, which is consistent with structure XV, which has an empirical formula of C H O In addition, the nuclear magnetic resonance spectra of the two isomers were essentially identical as were the infrared and ultraviolet spectra. Further, either isomer can be oxidized to the original ketone by treatment with manganese dioxide.

Example 15 To a solution of 0.064 g. of the mixture of diastereoisomers from Example 14 in 30 ml. of acetone was added 0.0280 g. of p-toluenesulfonic acid. This mixture was then concentrated on a rotary evaporator in an ice bath at 10 mm. pressure. The time required for evaporation was approximately seven minutes. To the residue was added 6.4 m1. of acetone and the solution was spotted directly on a thin-layer chromatography plate. The chromatogram indicated no reaction had taken place. The volume was made up to 30 ml. by the addition of acetone and the mixture was again concentrated, this time at 27 C. To the residue was added 6 ml. of acetone and again the solution was spotted directly on a thin-layer chromatography plate. This chromatogram showed no starting material. The solution was stripped to dryness, the residue was extracted with ether, the ether extract was washed once with 50 ml. of saturated sodium bicarbonate and twice with 50 ml. of saturated sodium chloride solution, dried over sodium sulfate, and evaporated to give 57 mg. of a yellow oil. Chromatography on florisil at a ratio of 1:430 using initially a solvent consisting of 10 percent chloroform and percent benzene and slowly increasing chloroform to percent resulted in the isolation of 27 mg. of a fastmoving material and 47 mg. of a slower-moving material. This slower-moving material absorbed at 233 nanometers and 278 nanometers. These two absorption bands were ascribed to the positions of the double bonds in the isomeric compounds XVI and XVII. Further purification by preparative thin-layer chromatography gave a single-spot material which was shown by high resolution mass spectrometry to have a molecular weight of 350. This molecular weight is that expected for a compound having the Formula C H O Example 16 To a solution of 0.142 g. of the ketal X'IV in 50 ml. of acetone'was added 0.142 g. of p-toluenesulfonic acid. The system was flushed several times with nitrogen and the reaction mixture was heated under reflux in a nitrogen atmosphere for 24 hours. The mixture was extracted with ether and the ether extract washed with saturated sodium chloride solution, dried over sodium sulfate, and evaporated to give mg. of yellow oil. The yellow oil was chromatographed on silica at a ratio of 1:32 using 20 percent chloroform, 80 percent benzene as solvent to give 52 mg. of a product which showed to be single-spot material by thin-layer chromatography. The infrared, ultraviolet, and nuclear magnetic resonance spectra of the product were consistent with the expected structure XXI. In addition, the molecular weight as determined by high resolution mass spectrometry was the expected 348.

Analysis-Calculated for C H O C, 72.38; H, 9.26; O, 18.37. Found (percent): C, 71.70; H, 9.30; O, 18.12.

It is to be understood that Compound )Ofl can be hydrolyzed to the free acid. Such hydrolysis is well within the skill of a trained chemist. It is also to be understood that Compound XXI may be prepared in other ways and that other compounds may be obtained from the intermediate of our process. For example. Compound )Qfl may be obtained by the oxidation of the hydroxyl group in the side chain of Compound XVL This oxidation may be accomplished by the use of a mild oxidizing agent such as manganese dioxide.

Example 17 A solution of 0.182 g. of the diketone XXI in 20 ml. of tetrahydrofuran freshly distilled from lithium aluminum hydride was cooled to 74 C. in a Dry Ice/isopropanol bath. To this cooled solution was added a solution of 0.140 g. of lithium aluminum tri-t-butoxy hydride in 20 ml. of freshly distilled tetrahydrofuran over a 13-minute period, with stirring and under nitrogen. Stirring was continued under nitrogen at -74 C. for one hour. The mixture was then warmed to room temperature and held there for 30 minutes. The product was extracted from the mixture with ether, the ether extract was washed with saturated sodium chloride solution, dried over sodium sulfate, and evaporated to give 158 mg. of a brown oil. The product was purified by chromatography over silica using a 20 percent chl'oroform/ 80 percent benzene solvent and a product to silica weight ratio of 1:11. The infrared and ultraviolet spectra were consistent with structure XXII and the molecular weight of 350 was confirmed by mass spectroscopy.

In the course of our work we have discovered a method for the preparation of the naturally occurring prostaglandin, PGB and in addition have prepared two heretofore unknown synthetic prostaglandins, Compounds XVI and XXII. These two new prostaglandins have the formulae:

| fiwnmcozcm (011060020113 XVI XXH It is to be understood that these compounds may exist as free acids, or the methyl group may be replaced by such equivalent groups as ethyl, propyl, t-butyl, nonyl, 2,2,2- trichloroethyl, benzyl, and diphenylmethyl. Additional equivalent ester groups will be apparent to those skilled in the 'art. It is further understood that pharmaceutically acceptable salts, such as the sodium or potassium salts, may be employed in place of the acids or esters.

These new prostaglandins exhibit many of the desirable characteristics of the prostaglandin family but surprisingly are free from many of the undesirable effects. For example, both these compounds cause a marked decrease in blood pressure, which is characteristic of the prostaglandins; however, neither compound causes contraction or relaxation of smooth muscle tissue, which is another characteristic of the naturally occurring prostaglandins.

The efiect of Compounds XVI and XXII on the blood pressure of an anesthetized rabbit was determined according to standard procedures. The animals employed were male New Zealand White rabbits anesthetized with urethane (1.25 g. 1 kg.) or Nembutal (25 mg. 1 kg.). The animal was prepared for recording of blood pressure using the Statham pressure transducer. The compound was dissolved in ethanol-water and the solution was administered via the femoral vein. Results are given as follows: (a) mean blood pressure just prior to administration of the compound; (b) mean blood pressure after administration;

and (c) the change in blood pressure. The results are summarized in the following table.

In addition to being a prostaglandin in its own right, Compound XVI is also a useful intermediate in the prep aration of the naturally occurring prostaglandin, PGB

We claim:

1. A synthetic prostaglandin consisting essentially of a compound having the formula wherein R is hydrogen or methyl.

2. A synthetic prostaglandin having the formula wherein R is hydrogen or methyl.

References Cited UNITED STATES PATENTS 1/ 1972 Gordon et al. 260-468 OTHER REFERENCES Clones, Proceedings of the British Pharmacological Society, Mar. 28-29, 1972.

LORRAINE A. WE-INBERGER, Primary Examiner R. GERSTL, Assistant Examiner US. Cl. X.R. 

